Restless Legs Syndrome
Restless legs syndrome (RLS) is a distinctive but often misdiagnosed sensorimotor disorder. The general incidence of RLS is high and is the seventh most frequently diagnosed musculoskeletal disorder out of 103 diagnoses relating to these conditions [Arch. Intern. Med., 161, 483-484 (2001)]. RLS is also characterized as a sleep disorder and is frequently diagnosed as a cause of insomnia [Sleep Med., 2, 367-369 (2001); and Sleep, 23, 237-241 (2000)].
Although RLS was first described in the 17th century, the classic features that define the syndrome were first presented in 1945 [The London practice of Physick. London: Bassett et al. Eds. (1962); and Acta Med. Scand. Suppl., 158, 1-123 (1945)]. Despite the number of years since RLS was first appreciated as a medical indication, diagnosis and treatment remain sub-optimal. Even though it may affect up to 10% of the US population, it is often unrecognized or misdiagnosed. In some cases, a cause can be found, such as iron-deficiency anemia, and the RLS can be cured. In general, however, motor restlessness is poorly diagnosed and treated [IJCP, 55, 320-322 (2001)].
Although the etiology of RLS is unknown, the primary anatomic localization of abnormal functioning in RLS is possibly in spinal system [Disord., 13(suppl 2), 294 (1998)]. Several new diagnostic tools may aid in identifying RLS [J. Neurol., 249, 164-170 (2002); and Clin. Neurophys., 113, 571-578 (2002)].
The features associated with RLS include dysesthesias deep in the limb that compel the person to move in order to relieve the sensation and that are engendered and exacerbated by rest, primarily in the evening and at night [HealthNews, Greene, Jun., 10 (2001)]. In 1995, the International RLS Study Group published the primary and associated features of this disorder [Mov. Dis., 10, 634-642 (1995)]. For recent reviews, see, Latorre & Irr (2001) http://www.emedicine.com/NEURO/topic509.htm; 2001 Medical Bulletin, Restless Legs Syndrome Foundation, Inc.; and Am. J. Med. Sci., 319, 397-403 (2000). Additional criteria of RLS include involuntary, rhythmic retraction movements occurring especially at night, and especially during sleep stages I and II; and sleep disturbance results in daytime fatigue.
Although RLS occurs as a component of several diseases, it is not indicative of these diseases [Sleep, 23, 361-367 (2000); Arch. Neurol., 59, 421-424 (2002); J. Neurol. Sci., 196, 33-36 (2002); and J. Neurol. Neurosurg. Psych., 72, 555 (2002)].
According to the Restless Legs Syndrome Foundation (www.rls.org), adults with RLS will typically have all four of the following primary features. First, the bothersome, but usually not painful, sensations deep in the legs produce an irresistible urge to move. Second, symptoms are worse or exclusively present when the afflicted individual is at rest, and the sensations are typically lessened by voluntary movement of the affected extremity. Third, symptoms are worse in the evening and at night, especially when the individual lies down. Fourth, movements of the toes, feet, or legs (known as restlessness) are typically seen when the afflicted individual is sitting or lying down in the evening. This restlessness may be seen as fidgetiness or nervousness.
The dysesthesias and accompanying urge to move occur most commonly during the evening or early part of the night (between 6 pm and 4 am) [Sleep, 22, 901-912 (1999); and Mov. Disord., 14, 102-110 (1999)]. Patients are less bothered by symptoms during the daytime and, even if severely affected, often obtain some relief near dawn. The symptoms progress over time in about two thirds of RLS patients and may be severe enough to be disabling, disrupting sleep and impacting on a patient's life and well-being.
Adults with RLS almost always describe these uncomfortable sensations or parenthesis, which most commonly occur in the legs, as being like an electric current, water moving, or insects crawling or as tingling, aching, or grabbing. A wide variety of other descriptions have been offered, and some patients cannot describe the sensations at all except as an urge to move the leg [Neurol., 47, 1435-1441 (1996)].
In a significant minority of individuals with RLS (perhaps 20% to 30%), similar sensations occur in the arms, usually in more severely affected patients later in the clinical course of their disorder [Eur. Neurol., 45, 67-74 (2001); and Eur. Neurol., 44, 133-138 (2000)]. Even less frequently, these sensations occur in the trunk or elsewhere. The sensations are not generally described as painful, but if asked directly, a minority (perhaps 20%) of patients will describe the sensations as painful.
The unpleasant limb sensations of RLS are precipitated by rest or inactivity such as lying in bed, riding in a car or airplane or sitting in a theater. Some patients describe increasing discomfort and involuntary limb jerking if they remain still. There is an urge to move the legs because relief is often gained after moving. To relieve the urge to move, patients typically walk around, although they may attempt to obtain relief through performing a wide variety of movements such as rocking, shaking, stretching, marching in place, pacing, or bending. Some patients obtain relief simply from standing.
These varied movements that patients select to reduce their symptoms are under voluntary control and can be suppressed on command. Suppression may greatly increase the patient's discomfort, however, and few severely affected individuals are capable of stifling their restless movements for more than a brief period when they are symptomatic. In rare cases, the movements may occur as the dominant symptoms with only very limited awareness of the urge to move.
In most cases, the cause of RLS is unknown. Such idiopathic disease can be familial and, if so, is transmitted in an autosomal dominant fashion. Progressive decrease in age at onset with subsequent generations has been described in some families. Patients with familial RLS tend to have an earlier age at onset and slower progression. Despite the use of dopaminergic agents to treat RLS, the genes involved in dopaminergic neurotransmission were found to have no influence on RLS [Neurol., 57, 1304-1306 (2001)].
Associated Features of RLS
RLS symptoms can cause difficulty in falling and staying asleep resulting in abnormal tiredness during waking hours. Chronic sleep deprivation and its resultant daytime sleepiness can affect the patient's ability to work, participate in social activities, and partake in recreational pastimes and can cause mood swings, which can affect their personal relationships.
RLS may be the result of another condition, which, when present, worsens the underlying RLS. This is called secondary RLS. During pregnancy, particularly during the last few months, up to 15% of women develop RLS. After delivery, their symptoms often vanish. Other causes include the following. Deficiency of iron, folate, B-12 or magnesium. Iron, folate and B-12 deficiencies can result in anemia. Magnesium deficiency is rare except in the presence of unusual diets. RLS can be the initial symptom of iron deficiency. Polyneuropathy can also lead to RLS. Polyneuropathy can be caused by alcohol abuse, amyloidosis, diabetes mellitus, lumbosacral radiculopathy, Lyme disease, rheumatoid arthritis, uremia or vitamin B-12 deficiency. Gastric surgery, which can lead to mal-absorption of foods. Chronic obstructive pulmonary disease (COPD) which can lead to changes in blood chemistry such as acidosis or alkalosis, low oxygen saturation, or retention of carbon dioxide. These changes in the blood chemistry can, in turn, irritate the peripheral nerves and result in RLS. Chronic venous insufficiency or varicose veins. Intake of certain drugs such as alcohol, caffeine, anticonvulsants, antidepressants, beta blockers, lithium or certain major tranquilizing agents. Abrupt withdrawal from certain drugs such as vasodilators, sedatives or antidepressants. Myelopathy or myelitis. Hypothyroidism or hyperthyroidism. Hypoparathyroidism or hyperparathyroidism. Acute intermittent porphrya. Liver failure. Cancer.
Though RLS is diagnosed most often in people in their middle years, many individuals with RLS, particularly those with primary RLS, can trace their symptoms back to childhood. These symptoms may have been called growing pains or the children may have been thought to be hyperactive because they had difficulty sitting quietly.
No laboratory test exists that can confirm a diagnosis of RLS. However, a thorough physical examination, including the results of necessary laboratory tests, can reveal temporary disorders, such as iron deficiency, that may be associated with RLS. Some patients will require an overnight testing of sleep to determine other causes of their sleep disturbance.
Treatment
If an underlying iron or vitamin deficiency is found to be the cause of a patient's restless legs, supplementing with iron, vitamin B12, or folate (as indicated) may be sufficient to relieve the symptoms. Current recommendations include checking a serum ferritin level (to evaluate iron-storage status) and supplementing with iron if the ferritin level is less than 50 μg/L. Patients with varicose veins have been found to benefit from use of sclerosing agents. Those with uremia may have relief after kidney transplantation or correction of anemia with erythropoietin.
The use of some medications seems to worsen the symptoms of RLS. These drugs include calcium-channel blockers, most antinausea medications, some cold and allergy medications, major tranquilizers, phenytoin, and most antidepressants.
Unfortunately, in many cases, the symptoms of RLS either initially do not resolve with the treatment of underlying disorders and the implementation of lifestyle changes or, over time, progress so that relief is insufficient with these methods. In either case, the use of medications may become necessary.
No drugs have been approved by the U.S. Food and Drug Administration for the treatment of RLS, but several drugs have undergone clinical studies in RLS and have been approved for other conditions. These medications fall into four main classes-dopaminergic agents, sedatives, pain relievers, and anticonvulsants. Each drug or class of drugs has its own benefits, limitations, and side-effect profile. The choice of medication is dependent upon the timing and severity of symptoms. Generally, treatment begins with a low dose taken an hour or two before bedtime. If tolerance to one drug develops, another class of drugs may be substituted.
Dopaminergic Agents
The primary and first-line treatment for RLS is with a dopaminergic agent [Expert Opin. Investig. Drugs, 11, 501-514 (2002); Neurol., 58(Suppl. 1), S87-S92 (2002); and Danek et al. In Neurological Disorders: Course and Treatment Academic Press, pp. 819-823 (1996)]. Involvement of altered activity of dopaminergic diencephalic spinal neurons that originate in A11 region [Brain Res., 342, 340-351 (1985)].
Although dopaminergic agents are used to treat Parkinson's disease, RLS is not a form of Parkinson's disease [J. Neurol. Sci., 196, 33-36 (2002)]. All of these drugs should be started at low doses and increased very slowly to decrease potential side effects. Due to the disabling side effects associated with long-term dopaminergic activation, chronic use of this class of drugs in RLS has not been adopted.
A variety of dopaminergic agents have been described for treating RLS. These include carbidopa, levodopa, carbidopa with levodopa (Sinemet), ropinerole, pramipexole, cabergoline, entacapone and, Piribedil [Mov. Dis., 17, 421 (2002); Mov. Dis., 16, 579-581 (2001); Eur. Neurol., 46(suppl 1), 24-26 (2001); U.S. Pat. Nos. 6,194,445; 6,114,326; 6,001,861; 5,945,424; and U.S. patent application No. 2001/0029262].
Dopaminergic agents can cause the side effect known as augmentation or rebound. Augmentation comprises an earlier onset of symptoms in the evening than before treatment, appearance of symptoms during the day, involvement of other body parts and an increased severity of symptoms. The only recourse is to stop taking the drug. Other side effects include nausea, dizziness, somnolence, insomnia, constipation, postural hypotension, asthenia and hallucination.
Sedatives
Sedative agents are most effective for relieving the nighttime symptoms of RLS. They are used either at bedtime in addition to a dopaminergic agent or for individuals who have primarily nighttime symptoms. The most commonly used sedative is clonazepam (Klonopin). Other suggested medications such as anti-histamines and NK1-receptor antagonists may function via their sedative effect.
Pain Relievers
Pain-relieving drugs are used most often for people with severe relentless symptoms of RLS. Some examples of medications in this category include codeine, Darvon or Darvocet (propoxyphene); Dolophine (methadone); Percocet (oxycodone); Ultram (tramadol); and Vicodin (hydrocodone). Opioids have been found to be the most effective at relieving symptoms, and relief has been found with intrathecal delivery of morphine or bupivacaine [Acta Anaesthesiol. Scand., 46, 114-117 (2002)]. Opioids are potent suppressors of RLS and PLMS, but the risks of abuse and addiction limit their use. Side effects and adverse reactions include dizziness, sedation, nausea, vomiting, constipation, hallucination and headache.
Anticonvulsants
These drugs are particularly effective for some, but not all, patients with marked daytime symptoms, particularly people who have pain syndromes associated with their RLS. Gabapentin (Neurontin) is the anticonvulsant that has shown the most promise in treating the symptoms of RLS [Neurol., 57, 1717-1719 (2001)].
Other Therapies
Other suggested treatments include transcutaneous electrical nerve stimulation, conditioning therapy, and various procedures to reduce incompetent veins, but none of these ancillary treatments has been clearly established to be effective [Health Technol. Assess., 1, 1-135 (1997); Sleep, 19, 442-444 (1996); and Dermatol. Surg., 21, 328-332 (1995)].
In particular, the Edinburgh vein study found that most lower-limb symptoms (including RLS) probably have a nonvenous cause and surgical intervention (i.e., sclerotherapy or “vein stripping”) is unlikely to alleviate the symptoms [Brit. Med. J., 318, 353-35 (1999)]. One group advocates medical therapy for what they call “hypotonic phlebopathy” (a mild form of venous insufficiency), but their clinical description coincides with the symptoms of RLS almost perfectly [Minerva Cardioangiol., 48, 277-285 (2000)].
Additional pharmaceutical agents have been proposed to treat RLS. These include 5HT antagonists; α2 antagonists such as Mirtazapine; NK1-receptor antagonists; anti-histamines; and an herbal extract of Valeriana [Neurol., 53, 1154 (1999); U.S. Pat. Nos. 6,346,283; 6,329,401; 6,319,927; 6,281,207; 6,214,837; and U.S. patent application Nos. 2002/0035057; 2001/0034320; 2002/0010201]. Mirtazapine, however, may cause RLS [Psych. Clin. Neurosci., 56, 209-210 (2002)].
Children
Recent literature also points toward an association between RLS and symptoms of attention-deficit hyperactivity disorder [Sleep, 25, 213-218 (2002)]. A few case reports and one case series have assessed treatment specific to children. These case reports have indicated individual responses to strict limit-setting in enforcing the child's sleep schedule, restricting caffeine consumption, and using medications such as clonazepam, carbidopa/levodopa, pergolide, or clonidine [Picchietti In Wilson, ed. Sleep thief: restless legs syndrome. Orange Park, Fla.: Galaxy Books pp. 82-94 (1996); Pediatr. Neurol., 22, 182-186 (2000); Sleep Res., 22, 70 (1993); Pediatr Neurol., 11, 241-245 (1994); and Sleep, 22, 297-300 (1999)].
Benzodiazepines, anticonvulsants, alpha-adrenergic agents, and opioids have been extensively used in children with disorders other than RLS, as has chronic use of levodopa for dopa-responsive dystonia [J. Am. Acad. Child Adolesc. Psych., 33, 424-426 (1994); and Neurol., 41, 174-181 (1991)]. An open-label trial of pergolide in the treatment of RLS in five children with RLS found that not only the sleep parameters, but also the children's scores of attention and impulsivity, improved [Pediatr. Neurol., 22, 182-186 (2000)].
PLMS
About 80% of patients with RLS have unilateral or bilateral periodic limb movements of sleep (PLMS), also called nocturnal myoclonus. Patients without RLS also experience PLMS. These movements are stereotyped, repetitive, slow flexion of the limbs (legs alone or legs more than arms) during the early stages of sleep. The movements occur semirhythmically at intervals of 5 to 60 seconds and last about 1.5 to 2.5 seconds. In the lower limbs, repetitive dorsi flexion of the big toe with fanning of the small toes is seen, along with flexion of the ankles, knees and thighs. Arm movements usually consist of the flexion of the forearm in combination with the wrist. There can be night-to-night variability in the number of movements.
PLMS can occur while patients are awake and are called dyskinesias. Such dyskinesias are uncommon but can occur in up to 50% or RLS patients.
PLMS increases with age. Thirty five percent or more of people aged 65 and older experience PLMS. PLMS also occurs in younger people, though less commonly. Men and women are equally affected. The exact cause of PLMS is still unknown. The underlying mechanisms probably involve factors in the nervous system, although studies have not revealed any consistent abnormalities.
PLMS are not considered medically serious. They can, however, be implicated as a contributing factor in chronic insomnia and/or daytime fatigue because they may cause awakenings during the night. Occasionally, PLMS may be an indicator of a serious medical condition such as kidney disease, diabetes or anemia.
A number of medications have been shown to be effective in treating PLMS, but treatment is only necessary when PLMS are accompanied by restless legs (RLS), insomnia or daytime fatigue.
Adenosine A2A Receptors
Adenosine is known to act via four major receptor subtypes, A1, A2A, A2B, A3, which have been characterized according to their primary sequences [Pharmacol. Rev., 46, 143-156 (1994)]. Adenosine A2A receptors are abundant in the caudate-putamen, nucleus accumbens, and olfactory tubercle in several species [Brain Res., 519, 333-337 (1990)]. A variety of A2A receptor antagonists have been synthesized (U.S. Pat. Nos. 6,262,106; 6,222,035; 6,197,788; 5,756,735; 5,703,085; 5,670,498; 5,565,460; and 5,484,920).
In the caudate-putamen, adenosine A2A receptors are localized on several neurons and have been shown to modulate the neurotransmission of γ-aminobutyric acid (GABA), acetylcholine and glutamate [J. Neurochem., 66, 1882-1888 (1996); J. Neurosci., 16, 605-611 (1996); Neuroscience, 100, 53-62 (2000); Trends Pharmacol. Sci., 18, 338-344 (1997); and Biosci. Biotechnol. Biochem., 65, 1447-1457 (2001)]. These actions of the A2A receptor contribute to the control of motor behavior since A2A receptor agonists inhibit locomotor activity and induce catalepsy in rodents [Adv. Neurol., 80, 121-123 (1999); and Psychopharmacology, 147, 90-95 (1999)]. In contrast, adenosine A2A receptor antagonists prevent the motor disturbances of dopamine D2 receptor null mice [J. Neurosci., 20, 5848-5852 (2000)].
A2A receptor antagonists have been evaluated in parkinsonian monkeys and found to be effective at treating symptoms of Parkinson's disease [Ann. Neurol., 43, 507-513 (1998); NeuroReport, 9, 2857-2860 (1998); and Exp. Neurol., 162, 321-327 (2000)]. It was demonstrated that the adenosine A2A receptor antagonist KW-6002 exhibits antiparkinsonian activity without producing hyperactivity and provoking dyskinesia [Neurology, 52, 1673-1677 (1999)].
More recently, the neuroprotective effect of an adenosine A2A receptor antagonist KW-6002 has been demonstrated in MPTP-induced dopaminergic neurodegeneration [J. Neurochem., 80, 262-270 (2002); and J. Neurosci., 21, RC143(1-6) (2001)].